Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction that doubles its late mortality. It is fundamentally caused by distortion of the damaged heart wall, which pulls on the mitral valve leaflets and restricts their ability to close. We have shown this process can be reversed by re-shaping the heart surgically or with an external patch; these approaches, however, immobilize a large portion of the heart and require open-heart surgery. We propose exploring two innovative ways to achieve this goal with additional benefits to the patient: (1) tissue regeneration by autologous myoblast transplantation into the infarcted wall, which, by becoming thicker, would resist deformation and assume a more normal shape that relieves the tension on the mitral leaflets (an approach with potential for minimally invasive implementation); and (2) using an external patch composed of polymer-based artificial muscle to provide both normal shape (less MR) and the additional benefits of contraction and relaxation to assist heart function. The artificial muscle development will require computational, in vitro and in vivo testing of alternative materials and designs. Both approaches will be tested in established models of ischemic MR with appropriate controls. These studies are justified by promising results with passive patches, and require exploratory work to develop functional patches. To achieve this synthesis of clinical problem and developmental techniques, this proposal will bring together expertise in several areas: quantitative analysis of the mitral valve in animal models by three-dimensional echocardiography, available in both Boston and Paris laboratories; myoblast harvesting and myocardial repopulation (Professor Menasche); developing innovative approaches to create artificial muscle (Professor Hunter at MIT); and cardiovascular surgery (Dr. Vlahakes and Prof. Menasche).